CN1061962A - Indenoindole compounds - Google Patents

Indenoindole compounds Download PDF

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CN1061962A
CN1061962A CN91110834A CN91110834A CN1061962A CN 1061962 A CN1061962 A CN 1061962A CN 91110834 A CN91110834 A CN 91110834A CN 91110834 A CN91110834 A CN 91110834A CN 1061962 A CN1061962 A CN 1061962A
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cis
methyl
indoles
indeno
tetrahydrochysene
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M·塞恩斯伯里
H·舍特泽
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Bath (gb) Claverton Down Bath Ba2 7ay England, University of
University of Cincinnati
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Bath (gb) Claverton Down Bath Ba2 7ay England, University of
University of Cincinnati
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Priority claimed from GB909022453A external-priority patent/GB9022453D0/en
Priority claimed from GB909027895A external-priority patent/GB9027895D0/en
Application filed by Bath (gb) Claverton Down Bath Ba2 7ay England, University of, University of Cincinnati filed Critical Bath (gb) Claverton Down Bath Ba2 7ay England, University of
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

General formula be cis condensed compounds, enantiomorph and the salt thereof of I be new, in medical science and non-medical field good antioxidant all.
Figure 91110834.3_AB_0
Here R is a methoxy or ethoxy, when R is methoxyl group, and R 1Be methyl and R 2And R 3All be hydrogen or all be methyl; When R is oxyethyl group, R 1Be hydrogen and R 2And R 3It all is methyl.

Description

Indenoindole compounds
The present invention relates to new Indenoindole compounds, they are hydrophobic antioxidants, and very effective to reduction (being quenching) free radical in lipid and lipid two-phase, therefore can stop the peroxidation process of lipid, avoid the disease that causes by this and relevant process.The invention still further relates to composition, especially comprise at least a invention compound or its salt in the composition, acceptable salt was as the pharmaceutical composition of activeconstituents during especially it was treated.Furtherly, the present invention relates to the preparation method of these compounds, active compound is in therapeutic treatment and prevention and in the application aspect the non-medical.The application of particularly important is control or the mediation process that stops free radical in the non-medical field.
Some bioprocesss produce some stable intermediates more or less, and these intermediates contain unpaired electron, they or provide away, perhaps with other electron pairing on every side.Such intermediate is called free radical.They may be the products of various enzymic catalytic reactions or non-enzymatic catalysis reaction, and some of them are extremely important to physical function (for example for synthetic DNA reduction nucleoside diphosphate, generating prostaglandin(PG) in the prostaglandin synthase reaction).Inflammation and other several functions after latter's pair cell destroys are essential.The reaction of other group comprises can killing bacteria and the neutrophils of other invasion particle and the transfer that the myeloperoxidase enzyme reaction in the scavenger cell reaches electronics on mitochondrial respiratory chain.Most of organisms contain chemical antioxidants, as: alpha-tocopherol (vitamin-E), xitix, other base and peroxidation deactivating enzyme such as superoxide dismutase, catalase and Selenoperoxidase.
Various types of free radicals and numerous disease have increasingly extensive getting in touch, these diseases are decreased part as: local asphyxia, atherosclerosis, thrombosis and embolism, the aging as bronchial asthma of supersensitivity/inflammatory, rheumatoid arthritis, and presenile dementia diseases associated, Parkinson's disease and aging, cataract, diabetes, tumour, antitumor drug poisoning, immunosuppressor poisoning, chemical substance poisoning etc.A kind of possible still unknown explanation to these diseases is: resist and give birth to the destruction that protectant activity is not enough to protective tissue opposing base in the basic destructive.In above-mentioned disease, the lipid peroxidation that is caused by the excessive generation of base may constitute an important destruction approach.In addition, take the antioxidant that can suppress radical reaction (as lipid peroxidation) and can prevent and cure above-mentioned disease.The invention describes the new antioxidant of indenoindole, they can satisfy the needs that accumulate in the film is that they have enough hydrophobicitys, is again effective inhibitor of lipid peroxidation.These new antioxidants can compare with other antioxidant such as alpha-tocopherol well.The compounds of this invention also can be used for stable compound to the deterioration by oxidation sensitivity aspect non-medical, as skin care product, and food antiseptic, the protection of foodstuff additive and other article.The invention provides a kind of resistates compound and carry out method of stabilizing with tetrahydroindene diindyl and gained.
We patent application PCT/GB 90/00949(in the past delivers on international patent specification (International Specification) wo 90/15800 in December 27 nineteen ninety) be about one group of tetrahydrochysene indenoindole compounds, they are a kind of effective inhibitors in the lipid peroxidation process, and can be used as antioxidant.
According to the present invention, it provides cis condensed compounds, enantiomorph and the salt thereof of formula I.
Figure 911108343_IMG7
Ⅰ
Wherein R is a methoxy or ethoxy, when R is methoxyl group, and R 1Be methyl and R 2And R 3All be hydrogen or all be methyl; When R is oxyethyl group, R 1Be hydrogen and R 2And R 3It all is methyl.
Finding that the cis melting compound with tetrahydroindene diindyl structure of formula I is the highly efficient depressor of lipid peroxidation process, also is a kind of useful antioxidant.Compound with formula I can be a kind of racemic mixture, pure enantiomorph or its mixing.
The compounds of this invention can be particularly useful as the antioxidant in the medical treatment.
Numbering is as follows in the indole structure ring of the present invention:
Figure 911108343_IMG8
Cis-4b, 5,9b, 10-tetrahydrochysene indeno [1,2-b] indoles (THII)
The tetrahydroindene diindyl with formula I that comprises in the present invention is as follows:
Cis-4b, 5,9b, 10-tetrahydrochysene-4b, 6,7,9,9b-pentamethyl--8-methoxyl group-indeno [1,2-b] indoles
Cis-4b, 5,9b, 10-tetrahydrochysene-8-oxyethyl group-4b, 7,9,9b-tetramethyl--indeno [1,2-b] indoles
Cis-4b, 5,9b, 10-tetrahydrochysene-8-methoxyl group-6,7,9-trimethylammonium-indeno [1,2-b] indoles
According to the present invention, pharmaceutical preparation or the common through port of other pharmaceutically acceptable formulation, rectum, skin or drug administration by injection that the cis condensed compounds of formula I is an activeconstituents with its free alkali or pharmaceutically acceptable non-toxic acid additive salt, the example of its acid salt has hydrochloride, hydrobromate, lactic acid salt, acetate, phosphoric acid salt, vitriol, sulfamate, Citrate trianion, tartrate, oxalate etc.Its preparation can contain pharmaceutically acceptable carrier or thinner.
Formulation can be solid, semisolid or liquid preparation.Usually active substance will account for 0.1 to 99% of weight of formulation.Specifically, during injection, active substance accounts for 0.5 to 22% of weight of formulation, and when oral, active substance accounts for 0.2 to 50% of weight of formulation.When percutaneous drug delivery was taken, active ingredient accounted for 0.1 to 5% of weight of formulation usually, and used suitable carrier.
The pharmaceutical preparation that contains invention compound dosage unit form that the desire preparation is for oral use, can be earlier with selected compound and a kind of solid excipient, a kind of tackiness agent and a kind of mix lubricant, be pressed into tablet then, used vehicle such as lactose, sucrose, sorbyl alcohol, mannitol, starch such as potato starch, W-Gum or amylopectin, derivatived cellulose; Tackiness agent such as gelatin or polyvinylpyrrolidone, lubricant such as Magnesium Stearate, calcium stearate, polyoxyethylene glycol, wax, paraffin etc.If need be coated with the stain tablet, the core coating priming that aforesaid method can be produced, liquid glucose can contain gluing, gelatin, talcum, titanium dioxide and congener.In addition, tablet also can apply the polymkeric substance that is soluble in volatile organic solvent or ORGANIC SOLVENT MIXTURES well known by persons skilled in the art.Pigment can be added in the coating so that distinguish the different tablet tablets different of active substance with active compound content.
For soft capsule preparation, active substance can be with mixed as vegetables oil or polyoxyethylene glycol.Hard capsule can contain active material particle and use any vehicle such as lactose, sucrose, sorbyl alcohol, mannitol, starch such as potato starch, W-Gum or amylopectin, derivatived cellulose or the gel that uses in the above-mentioned tablet.Liquid or semi-solid state medicine also can be put into hard capsule.
The dose unit that is used for rectal administration can be solution, suspension, also can make with active substance and neutral fat alkali blended suppository form or with active substance and vegetables oil or the mixed rectum capsule of paraffin oil.
Being used for oral preparation can be slurries or suspension, as contains about 0.2% to the 20%(weight percent) active substance, remaining material is the solution of sugar and ethanol, water, glycerine and propylene glycol mixture.These liquid preparations can contain tinting material, odorant, asccharin and carboxymethyl cellulose thickener or other vehicle well known by persons skilled in the art.
The solution that is used for the injection of non-enteron aisle can prepare with the aqueous solution of the pharmaceutically acceptable water-soluble salt of active substance, and volt selects concentration to be about 0.5% to 10%(weight percent).These solution can also contain stablizer and/or buffer reagent and can be contained in easily in the ampoule of various dose units.
Per daily dose suitable when The compounds of this invention is used for human body therapy is about: each about 0.01-100mg/kg body weight of oral medication, non-enterally administer, 0.001-100mg/kg body weight.
The compounds of this invention can prepare by the following method, but invention is not limited only to these methods, and these compounds can prepare with the method that known technology is described.
A.R 2And R 3All be the 4b of hydrogen, 5,9b, 10-tetrahydrochysene indeno [1,2-b] indoles (I A) can be corresponding 5 by reduction, 10-dihydro indeno [1,2-b] indoles (DHII) preparation.
Figure 911108343_IMG9
Wherein R and R 1Define as formula I.
The DHII raw material by with boryl reductive agent such as sodium cyanoborohydride a kind of solvent normally in the acetate reaction or with tetrahydrofuran (THF) in BH 3The reaction and be reduced.Can use under the situation that has the strong acid example hydrochloric acid to exist at the solvent morpholino borane in tetrahydrofuran (THF) or the dioxan normally.In addition, also available trialkyl silane.When reaction finished, by the dilute with water reaction mixture, the method for neutralization and filtration or solution extraction was isolated product.Also can finish reaction by the hydrogenation under catalyzer such as palladium effect.The DHII compound is dissolved in appropriate solvent such as ethanol, acetate or the ethyl acetate in this case.In the above-mentioned situation, by removing catalyzer, evaporating solvent is isolated product under the decompression state.
The THII compound can be purified or purify with silica gel column chromatography by crystallization from appropriate solvent.
B 4b, 9b-dimethyl-4b, 5,9b, 10-tetrahydrochysene indeno [1,2-b] indoles (I B) can be directly by with general formula being the pseudo-indole and the lithium methide (CH of III 3Li) in to the solvent of proton inert such as anhydrous tetrahydro furan, react and prepared.
C 4b, 9b-dimethyl-4b, 5,9b, 10-tetrahydrochysene indeno [1,2-b] indoles (I B) also can be replaced by a series of metals by the unsubstituted analogue of corresponding 4b-, as use butyllithium, use the carbonic acid gas carbonization, directly carry out the metal replacement and carry out alkyl with methyl halide or methyl sulfate replacing with butyllithium again, the N-carboxylation intermediate hydrolysis with gained at last makes.
The DHII raw material of general formula II can be the phenylhydrazine of IV and the 1-2 of general formula V by general formula, 3-bihydrogen-1-indenone (R 4Be hydrogen) carry out Fischer indoles building-up reactions and make.
General formula is that the pseudo-indole raw material of III can be the phenylhydrazine of IV and the 2-methyl-2 that general formula is V by general formula, 3-bihydrogen-1-indenone-(R 4Be methyl) prepared in reaction.
Figure 911108343_IMG11
Wherein R and R 1Define as formula I R 4Be respectively hydrogen or methyl.
General formula is the 1-or the 2-methyl-2 of V, the 3-bihydrogen-1-indenone can with general formula be the phenylhydrazine of IV to react this phenylhydrazine both can be free alkali, also can be salt, normally hydrochloride.Usually reactants dissolved is in solvent, preferred alcohols solvent such as ethanol or propyl alcohol.Need not heat in some cases, but make its backflow more than 1 hour or 1 hour must heating to reaction mixture under the other situation.
General formula is the compound of V and the reaction of phenylhydrazine that general formula is IV by general formula is that to form general formula be the compound of II or III for the phenylhydrazone intermediate of VI.
Figure 911108343_IMG12
Ⅵ
Wherein R and R 1Define as formula I R 4Be hydrogen or methyl.
The phenylhydrazone intermediate can come out or separates with method of extraction with appropriate solvent sometimes by dilute with water reaction mixture and filtering separation.Further purification can be by crystallization or chromatography.At last, can obtain satisfied effect with silica gel column chromatography and with a series of eluting solvents.
Phenylhydrazone is cyclized into the pseudo-indole that DHII that general formula is an II or general formula be III and can realizes by following steps: they are dissolved in a kind of appropriate solvent again, preferably a kind of alcohol such as ethanol or propyl alcohol are with a kind of sour example hydrochloric acid, acetate or trifluoroacetic acid treatment soln.May need heating also may not need to heat.Other cyclization reagent comprises Lewis acid such as zinc chloride or contains reagent such as phosphorus trichloride, phosphoryl chloride, Tripyrophosphoric acid or the polyphosphate of phosphorus atom.
With 2, in the reaction that the 3-bihydrogen-1-indenone carries out, should replace phenylhydrazine with phenylhydrazine salt, but the intermediate phenylhydrazone is cyclized into the reaction spontaneous generation of DHII or pseudo-indole.
Formula is the unsubstituted analogue of 4b-of the compound of I B, and promptly general formula is that the compound of VII can be the phenylhydrazine of IV and the 2-methyl-2 that general formula is V by general formula, 3-bihydrogen-1-indenone (R 4Be methyl) carry out Fischer indoles building-up reactions and then the reduction of the intermediate pseudo-indole of general formula III is made.
Figure 911108343_IMG13
Ⅶ
General formula is that the pseudo-indole of III is reduced in the reaction of the substituted derivative in C-9b position and can finishes as the sodium borohydride that is dissolved in the suitable solvent (as ethanol) with the standard reductive agent.Product separates with usual method and purifies then.
Such as 5,10-dihydro indeno [1,2-b] indoles (DHII) and the preparation method who contains the such raw material of the analogue of functional group describe in our application EP-A-0404536.
Principle of the present invention and suitability below are described, yet are not limited to this.The temperature that provides is degree centigrade.
Embodiment 1
Cis-4b, 5,9b, 10-tetrahydrochysene-4b, 6,7,9,9b-pentamethyl--8-methoxyl group indeno [1,2-b] indoles
ⅰ) 2,3,6-Three methyl Benzene methyl ether
50 gram (0.367mol) 2,3 that will be in the 500ml acetonitrile, 6-pseudocuminol, 55 gram (0.4mol) salt of wormwood and 36ml(0.38mol) mixture heating up of methyl-sulfate refluxes and spends the night.Add the 35ml strong aqua again, mixture refluxed 1 hour.After filtration and the evaporation, resistates is dissolved in ether, uses the sodium hydroxide solution washed twice, uses the sodium hydrogen carbonate solution washed twice again.Dry (MgSO 4) and evaporate 50.8 the gram products (92%).
ⅱ) 4-nitro-2,3,6-Three methyl Benzene methyl ether
20.3 gram (0.135mol) 2,3 in 200ml acetate to stirring and heat (70-80 ℃) splash into the dense HNO of 9.65ml in 20ml acetate in the 6-Three methyl Benzene methyl ether solution 3The aqueous solution.After the interpolation mixture is poured in the ice into dichloromethane extraction three times of the mixture of gained.Organic phase is evaporated to remove acetate and methylene dichloride; Resistates is dissolved in the ether and uses the sodium hydroxide solution washed twice, cleans twice with sodium hydrogen carbonate solution again.Dry (MgSO 4) also can get 19.0 gram (72%) products after the evaporation.Product can use without purifying in next step.
ⅲ) 4-amino-2,3,6-Three methyl Benzene methyl ether
19.0 gram (0.097mol) 4-nitros-2,3 that will be in 200ml ethanol, 6-Three methyl Benzene methyl ether and two little spoonfuls of pd/c(5%) mixture hydrogenation 4 hours in the Pa Er device.Remove by filter catalyzer and evaporating solvent.Resistates is dissolved in the ether and with aqueous hydrochloric acid (2M) and extracts.
It is 14 that the mixing water is basified to pH value with aqueous sodium hydroxide solution.The alkaline solution extracted with diethyl ether of gained.Dry (MgSo 4) after, add the Hcl(gram) diethyl ether solution, product salts out with its Hcl.Get 10.1 gram (63%) products after the filtration.
ⅳ) 4-diazanyl-2,3,6-Three methyl Benzene methyl ether
With 5.17 gram (0.0256mol) 4-amino-2,3,6-Three methyl Benzene methyl ether hydrochloride dissolves until hydrochloride in the suspension heating (80 ℃) of 30ml concentrated hydrochloric acid aqueous solution and 35ml water.Be cooled to-5 ℃, the hydrochloride fine crystals is separated out once more.1.77 gram (0.0256mol) NaNo that will be in 15ml water 2Added in 30 minutes in the stirred mixture, temperature of reaction remains on-5 ℃ to 0 ℃ simultaneously.After continuing to stir 15 minutes under this temperature, with 14.46 gram (0.064mol) Sncl 2X2H 2The solution of O in the dense Hcl aqueous solution of 12ml splashed in 15 minutes, and simultaneous temperature remains on zero degree.Then, slowly allow the temperature of reaction mixture reach room temperature again with sodium hydroxide solution with reaction mixture alkalize to pH value be 14.With gained mixture extracted with diethyl ether, dry (MgSo 4) after, add the Hcl(gram) diethyl ether solution, product is separated out with its hydrochloride.Can get 3.8 gram (69%) products after the filtration.
ⅴ) 9b, 10-dihydro-6,7,9,9b-tetramethyl--8-methoxyl group indeno [1,2-b] indoles
With 2.2 gram (0.012mol) 4-diazanyls-2,3,6-Three methyl Benzene methyl ether, 1.9 gram (0.013mol) 2-methyl-2, the mixture of the dense Hcl aqueous solution of 3-bihydrogen-1-indenone and 2ml in 20ml ethanol refluxed 1 hour under argon gas.The evaporation of cooling back removes desolvates, and resistates is distributed in the mixture of water and methylene dichloride.Add NaHCo at aqueous phase 3Aqueous solution neutralization also will respectively be separated.Dry (MgSo 4) and evaporate organic phase after, remaining thick product is purified with silica gel column chromatography and is made eluent with methylene dichloride.Can get the product of 1.1 grams 31% thus, next step can directly use.
ⅵ) cis-4b, 5,9b, 10-tetrahydrochysene-4b, 6,7,9,9b-pentamethyl--8-methoxyl group indeno [1,2-b] indoles
Under the argon atmospher, to 1.1 gram (0.0038mol) 9b of cooling (80 ℃), 10-dihydro-6,7,9, the lithium methide of the 1.6M of adding 4ml in ether in the 20ml anhydrous THF solution of 9b-tetramethyl--8-methoxyl group indeno [1,2-b] indoles.Mixture stirred 1 hour down at-78 ℃, and-20 ℃ were stirred 1 hour down.Temperature adds NH after reaching 0 ℃ 4The Cl aqueous solution and ether.To respectively be separated, organic phase washes with water once, dry (MgSo 4) and evaporation.The thick product of gained is purified with silica gel column chromatography, and makes eluent with ethyl acetate/octane-iso (2/10).Can get the product of the hope preparation of 0.3 gram (25%) thus.
1HNMR（CDCl 3）：1.41（3H，S）;1.43（3H，S）;1.96（3H，S）;2.07（3H，S）;2.35（3H，S）;3.0（1H，d）;3.55（3H，S）;3.65（1H，d）;7.1（3H，m）;7.25（1H，m）。
Embodiment 2
Cis-4b, 5,9b, 10-tetrahydrochysene-8-oxyethyl group-4b, 7,9,9b-tetramethyl-indeno [1,2-b] indoles
ⅰ) 4-nitro-2,6-dimethyl-1-phenetole
With 10 gram (0.0598mol) 4-nitros-2,6-xylenol, 16.5 gram (0.1196mol) K 2CO 3Refluxed 2.5 hours with the mixture of 18.6 gram (0.1196mol) iodoethanes in the 100ml acetonitrile.Solid matter is removed by heat filtering, then with hot acetonitrile washing.With the organic phase evaporation that merges, the gained resistates is dissolved in ether.Ether washes with water mutually, dry (Na 2SO 4) and the evaporation after can get 11.4 the gram (98%) product, M.P.56 ℃.
ⅱ) 3,5-dimethyl-4-phenetidine
With 11.4 gram (0.058mol) 4-nitros-2,115ml ethanol (95%) solution of 6-dimethyl-1-phenetole spends the night with the hydrogenation of pd/c catalyzer.Filter and remove catalyzer, solvent evaporated can get 9.2 gram (96%) products, M.P.74 ℃.
ⅲ) 3,5-dimethyl-4-oxyethyl group phenylhydrazine
9.2 gram (0.0557mol) 3 that stirred to refrigerative (+5 ℃) in 30 minutes, 5-dimethyl-4-phenetidine is at 50ml6NHCl(solution) suspension in be added in the gram of 3.8 in the 15ml water (0.0557mol) NaNo 2After further stirring 30 minutes under+5 ℃, the adding under argon atmospher and stirring of gained mixture is dissolved in 29.1 gram (0.167mol) sodium hyposulfates of 150ml water.+ 5 ℃ were stirred down after 20 minutes, added the 250ml ether, then with the sodium hydroxide solution of 10N with mixture alkalize to PH be 9.Separate organic phase and wash with sodium chloride solution.Dry (Na 2So 4) back adding HCl(gram)/ether (is 3 to pH value).Product is settled out with the form of hydrochloride.Filter and with the product that can get 9.4 grams (78%) after the ether washing.
ⅳ) 9b, 10-dihydro-8-oxyethyl group-7,9,9b-trimethylammonium indeno [1,2-b] indoles
With hydrochloride and 1.46 gram (0.01mol) 2-methyl-2 of 2.16 gram (0.01ml) 3.5-dimethyl-4-oxyethyl group phenylhydrazines, the 20ml acetic acid solution of 3-bihydrogen-1-indenone at room temperature stirs and spends the night, and refluxes then three hours.The dilute with water mixture, with the alkalization of the sodium hydroxide solution of 10N and with dichloromethane extraction three times, the organic phase of merging washes with water, drying (Na then 2So 4) the back evaporation can get the thick product of 2.8 grams, with petrol ether/ethyl acetate (5/1) recrystallization, can get 2.1 gram products (72%).M.P.164℃。
ⅴ) cis-4b, 5,9b, 10-tetrahydrochysene-8-oxyethyl group-4b, 7,9,9b-tetramethyl-indeno [1,2-b] indoles
Restrain (0.0063mol) 9b, 10-dihydro-8-oxyethyl group-7,9, dropping 10ml lithium methide (1.6N) diethyl ether solution in cold (78 ℃) solution of the 20ml anhydrous tetrahydro furan of 9b-trimethylammonium indeno [1,2-b] indoles in argon atmospher and under stirring to 2.0.Add and to finish the back and continue stirring 1 hour down, then restir 1 hour at room temperature at-20 ℃.Add the 20ml saturated ammonium chloride solution and make the reaction mixture quenching.After adding the 100ml ether, organic phase is separated, and with ammonium chloride solution washing reaction mixture twice, drying (Na 2So 4) and the evaporation can get 2.0 the gram (96%) products. 1HNMR（CDCl 3）：1.35（3H，t）;1.4（6H，d）;2.1（3H，S）;2.35（3H，S）;2.95-3.05（1H，d）;3.55-3.75（3H，m）;6.1（1H，S）;7.0-7.3（4H，m）。
Embodiment 3
Cis-4b, 5,9b, 10-tetrahydrochysene-8-methoxyl group-6,7,9-trimethylammonium indeno [1,2-b] indoles
ⅰ) 5,10-dihydro-8-methoxyl group-6,7,9-trimethylammonium indeno [1,2-b] indoles
1.95 gram (0.009mol) 4-diazanyls-2,3 that will be in 20ml ethanol, the hydrochloride of 6-Three methyl Benzene methyl ether (embodiment 1 is seen in its preparation) and 1.06 gram (0.008mol) 1-2, the mixture backflow of 3-bihydrogen-1-indenone solution and 2ml concentrated hydrochloric acid 1 hour.Solvent is removed in evaporation, and residuum is distributed between ether and the water.Water alkalizes with sodium hydroxide solution.Tell organic phase and wash with water.Dry (Na 2So 4) and the evaporation can get thick product, it is used chromatographic purification, make eluent with methylene dichloride/sherwood oil (20/80).Last recrystallization can get 1.08 gram (49%) products.
ⅱ) cis-4b, 5,9b, 10-tetrahydrochysene-8-methoxyl group-6,7,9-trimethylammonium indeno [1,2-b] indoles
To 0.65 gram (0.00234mol) 5,10-dihydro-8-methoxyl group-6,7,9-trimethylammonium indeno [1,2-b] indoles and 0.95 gram (0.00957mol) morpholine borane splash into the 1ml concentrated hydrochloric acid in 4ml dioxan solution.Mixture was refluxed 30 minutes, be cooled to room temperature, add the hydrochloric acid of 3ml6N.Mixture refluxed 30 minutes again.After being cooled to room temperature, crude mixture is allocated between ether and the aqueous sodium hydroxide solution.Tell organic phase and use aqueous sodium hydroxide solution and water washing.Dry (MgSo 4) also can get thick product after the evaporation.With its again from ethyl acetate/petroleum ether recrystallization promptly get 0.46 the gram (70%) product. 1HNMR（CDCl 3）：2.0（3H，S）;2.14（3H，S）;2.28（3H，S）;3.17（1H，dd）;3.55（1H，dd）;3.64（1H，S）;4.28（1H，ddd）;5.38（1H，d）;7.20-7.27（3H，m）;7.39（1H，d）。
Indenoindole compounds involved in the present invention has hydrophobicity and stable structure, and this structure can form positively charged ion, stable cation radical or oxide group.By measuring to external Fe 2+The inhibition of the lipid peroxidation that-ascorbate salt causes as can be known, they are good antioxidant, its IC 50Value is low to moderate 10nm.The compound of formula I can prevent the oxidation of the human plasma lipoprotein in rabbit smooth muscle cell or the mouse peritoneum scavenger cell effectively.They also can prevent local asphyxia/pour into the infringement to the isolation perfusion rat heart again, and can prevent tetracol phenixin, acetaminophen, methyl alkane sulfanilamide (SN), vitamin k4, tert-butyl hydrogen peroxide and N-methyl-N 1The caused damage of-nitrogen-N-nitrogen-Soguanidine to Mouse Liver or separation rats'liver.
These character show, The compounds of this invention can be used for preventing or treats local asphyxia or reperfusion injury, particularly face and cardiac ischemia or infraction, atherosclerosis, thrombus, embolism, Parkinson's disease, aging, the early ageing dementia, tumour and antitumor drug are poisoned, immunosuppressor and comprise the inflammation that causes as allergy such as bronchial asthma and rheumatic arthritis or inflammation.Other potential purposes comprises control chemical poisoning and radiation injury.Indenoindole compounds is difficult for for UV-activated, thereby can be used to make skincare product.The main characteristic that another of Indenoindole compounds of the present invention is interesting is to have the film stabilizing power.
The most significant characteristic of The compounds of this invention is its effect as radical scavenger or antioxidant.Adopt a mensuration that lipid peroxidation is suppressed 50%(IC 50) analytical system of required generalformula concentration.The mensuration of lipid peroxidation is described in the face 1 as follows, and data see Table 1.The inhibition test of the LDL-peroxidation that causes of scavenger cell is described in the face 2 as follows in addition, and data see Table 2.
1, ascorbate salt/Fe 2+The lipid peroxidation that relies on
For ferrous/ascorbate salt lipid peroxidation system, 6.25ml0.1M potassium phosphate buffer (KPi) (pH value 7.4) adds among the 12.5ml soybean phosphoric acid fat.With argon cleaning after two minutes, with suspension with five layers of Para film sealing and through acoustic treatment till suspension is transparent.Final reaction mixture is by 200 μ g/ml phosphatide, 10 μ mFeNH 4(SO 4) 2Or Fe(NH 4) 2(SO 4) 2With in 0.1mKPi(PH value 7.4) in 100 μ m xitix and after tested the polyphenoils in acetone or DMSO form.The volume of vehicle is no more than 1% of cumulative volume.Reaction begins by adding xitix and iron, at room temperature proceeds 30 minutes then in water-bath, and by adding 10 0.5M2s of μ m in DMSO, the 6-ditertbutylparacresol stops then.Said process and follow-up 2-thiobarbituric acid one reactive materials be determined at Shertzer, H.G et al, Biochem, Pharmacol.37 describes in 333(1988).Table 1 has provided indenoindole and alpha-tocopherol to ascorbate salt/Fe 2+Rely on lipid peroxidation.
Table 1
Compound P IC 50
Cis-8-methoxyl group-6,7,9-trimethylammonium-THII 8.0
Cis-8-oxyethyl group-4b, 7,9,9b-tetramethyl--THII 7.9
Cis-8-methoxyl group-4b, 6,7,9,9b-pentamethyl--THII 7.6
2, the inhibition of the LDL peroxidation that causes of scavenger cell
The mouse peritoneum scavenger cell contains in every milliliter of scavenger cell substratum on the HamShi F10 substratum of 25 μ g human low density lipoproteins (LDL) to be cultivated.The compounds of this invention is dissolved in the ethanol and is added to ultimate density 10 -5To 10 -10M.With the cell cultures of triplication 24 hours.Remove cell culture medium then.With Steinbrecher et al in Proc.Natl.Acad.Sci.USA, 81,3883(1984) the middle method of describing is analyzed peroxidation by the formation of measuring thiobarbituric acid reactive materials (TBARS).The result provides with the logarithmic form of concentration in table 2, and this concentration is to compare lipid peroxidation to reduce by 50% necessary concentration (PIC with control group 50).
Table 2
Compound P IC 50
Cis-8-methoxyl group-4b, 6,7,9,9b-pentamethyl--THII 7.9
Cis-8-ethoxy benzene-4b, 7,9,9b-durene-THII 7.8
Cis-8-methoxyl group-6,7,9-trimethylammonium-THII 7.9

Claims (9)

1, a kind of method for preparing cis condensed compounds, enantiomorph or its salt of formula I.
Figure 911108343_IMG2
Ⅰ
Here R is a methoxy or ethoxy, when R is methoxyl group, and R 1Be methyl and R 2And R 3All be hydrogen or all be methyl; When R is oxyethyl group, R 1Be hydrogen and R 2And R 3All be methyl, this method comprises:
A, 5, the reduction of 10-dihydro indeno [1,2-b] indoles (DHII)
Figure 911108343_IMG3
Wherein R and R 1Definition see claim 1.
B, usefulness lithium methide (CH 3Li) pseudo-indole of reduction general formula III
Figure 911108343_IMG4
C, for 4b, the 9b-dimethyl compound can be that the corresponding 4b-of VII is not substituted analogue and replaces by a series of metals by general formula, replaces by carbonic acid gas carbonization, metal and replaces with methyl halide or sulfuric acid methyl, last hydrolysis preparation.
Figure 911108343_IMG5
Ⅶ
2, according to the method for claim 1, prepare cis-4b, 5,9b, 10-tetrahydrochysene-8-oxyethyl group-4b, 7,9,9b-tetramethyl-indeno [1,2-b] indoles, enantiomorph or its salt.
3, according to the method for claim 1, prepare cis-4b, 5,9b, 10-tetrahydrochysene-8-methoxyl group-6,7,9-trimethylammonium indeno [1,2-b] indoles, enantiomorph or its salt.
4, according to the method for claim 1, prepare cis-4b, 5,9b, 10-tetrahydrochysene-8-methoxyl group-4b, 6,7,9,9b-pentamethyl-indeno [1,2-b] indoles, enantiomorph or its salt.
5, a kind of method of pharmaceutical compositions, it comprises pharmaceutically acceptable carrier and thinner and general formula is that the cis of I is thick and compound, enantiomorph or its pharmacy acceptable salt are formulated together.
Ⅰ
Here R is a methoxy or ethoxy, when R is methoxyl group, and R 1Be methyl and R 2And R 3Or all be methyl; When R is oxyethyl group, R 1Be hydrogen and R 2And R 3It all is methyl.
6, according to the method for claim 5, its formula of is that the cis condensed compounds of I is cis-4b, 5, and 9b, 10-tetrahydrochysene-8-oxyethyl group-4b, 7,9,9b-tetramethyl-indeno [1,2-b] indoles.
7, according to the method for claim 5, its formula of is that the cis condensed compounds of I is cis-4b, 5, and 9b, 10-tetrahydrochysene-8-methoxyl group-6,7,9-trimethylammonium indeno [1,2-b] indoles.
8, according to the method for claim 5, its formula of be the cis of I to condense chemical combination be cis 4b, 5,9b, 10-tetrahydrochysene-8-methoxyl group-4b, 6,7,9,9b-pentamethyl-indeno [1,2-b] indoles.
Thereby 9, by method with the stable compound to the deterioration by oxidation sensitivity of any compound that defines among the claim 1-4 or enantiomorph or the tactiosensible compound of its salt.
CN91110834A 1990-10-16 1991-10-15 Indenoindole compounds Pending CN1061962A (en)

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